RNase L Mediated Protection from Virus Induced Demyelination

Abstract

IFN-α/β plays a critical role in limiting viral spread, restricting viral tropism and protecting mice from neurotropic coronavirus infection. However, the IFN-α/β dependent mechanisms underlying innate anti-viral functions within the CNS are poorly understood. The role of RNase L in viral encephalomyelitis was explored based on its functions in inhibiting translation, inducing apoptosis, and propagating the IFN-α/β pathway through RNA degradation intermediates. Infection of RNase L deficient (RL−/−) mice with a sub-lethal, demyelinating mouse hepatitis virus variant revealed that the majority of mice succumbed to infection by day 12 p.i. However, RNase L deficiency did not affect overall control of infectious virus, or diminish IFN-α/β expression in the CNS. Furthermore, increased morbidity and mortality could not be attributed to altered proinflammatory signals or composition of cells infiltrating the CNS. The unique phenotype of infected RL−/− mice was rather manifested in earlier onset and increased severity of demyelination and axonal damage in brain stem and spinal cord without evidence for enhanced neuronal infection. Increased tissue damage coincided with sustained brain stem infection, foci of microglia infection in grey matter, and increased apoptotic cells. These data demonstrate a novel protective role for RNase L in viral induced CNS encephalomyelitis, which is not reflected in overall viral control or propagation of IFN-α/β mediated signals. Protective function is rather associated with cell type specific and regional restriction of viral replication in grey matter and ameliorated neurodegeneration and demyelination.

Structural basis for cytosolic double-stranded RNA surveillance by human oligoadenylate synthetase 1

“…Longer dsRNA elements might activate hOAS1, at least partially, if they become accessible to this sensor, and may have roles in connecting the 2-5A pathway to cell cycle, differentiation, and apoptosis (9)(10)(11)(12). Using bioinformatics we identified a plethora of dsRNA with 17 or more continuous base pairs in human mRNA, microRNA and long intergenic noncoding RNA (lincRNA) (Fig.…”

“…The 2-5A pathway serves as a conserved mammalian signal of viral presence providing resistance to hepatitis C virus (6), West Nile virus (7), and other RNA and DNA viruses (1,5,7,8). Broader roles of the 2-5A pathway in terminal differentiation of adipocytes (9), cell cycle (10), and BRCA1/IFN-γ-mediated apoptosis (11,12) have emerged recently.…”

Characterization of the termini of the West Nile virus genome and their interactions with the small isoform of the 2′ 5′-oligoadenylate synthetase family

“…RNase L deficiency in the case of this sub--lethal viral infection shows lethality and faster disease progression [249].…”

Enzymatic Pre-treatment of Wastewater to Minimize Recovery by Reverse Transcriptase PCR of RNA from Inactive Bacteriophages

“…Larger quantitative signal decay was measured for RNase 5 treatment (1.05 log units) than for the RNase1 treatment. On the other hand, the RNase 10 treatment might have been excessive and possibly reduced virus infectivity akin to mechanisms described for e.g., Rnase L [3]. This suggests that a maximum efficiency threshold was reached at B5 ng lL -1 .…”